Cancer is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood).
Lung cancer is a cancerous disease of uncontrolled cell growth in tissues of the lung. This growth may lead to metastasis, which is the infiltration and invasion of adjacent tissue and infiltration beyond the lungs. The vast majority of primary lung cancers are carcinomas of the lung, derived from epithelial cells.
Response to chemotherapy in lung cancer is comparatively low with about 10%-30% of patients having benefit from treatment, while having serious side effects and being costly for the national health systems. Despite responsiveness towards chemotherapy, the survival of lung cancer patients is still very poor. Lung cancer is the most lethal cancer in the world with estimated 215,000 new cases and 162,000 deaths per year in the US (Jemal, et al. 2008; 5 year overall survival: Stage I 50%, Stage IV 3%) in part due to the fact that most cases are detected in the later stages.
It is a well-established fact, that systemic treatment after surgery reduces the risk of disease relapse and death in patients with primary operable cancer. However, there still are a great number of patients who do not benefit from systemic therapy.
Prognostic factors in lung cancer include presence or absence of pulmonary symptoms, tumor size, cell type (histology), degree of spread (stage) and metastases to multiple lymph nodes, and vascular invasion.
There are only few data addressing the molecular prediction of response to therapy in lung cancer. Endocrine therapies have not been considered for early treatment of lung cancer so far mostly for several reasons: lung cancer is not a gynecologic tumor site, estrogens do not play a major role in lung development, significant (initial) response to chemotherapy and lack of stratification marker for endocrine therapies. This is in part due to the fact that the determination of hormone receptors and particularly ESR1 by immunohistochemistry failed to have prognostic value for lung cancer, while ESR2 determined on protein level may have some relevance in the comparatively small group of EGFR mutated tumors (Nose N, Sugio K, Oyama T, Nozoe T, Uramoto H, Iwata T, Onitsuka T, Yasumoto K.: Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung. J Clin Oncol. 2009 Jan. 20; 27 (3):411-7. Epub 2008 Dec. 8.).
This all is in sharp contrast to breast cancer, where the role of ESR1 mRNA and ER protein expression is well established as a stratification marker for endocrine treatment options.
In sharp contrast to, e.g., Nose, et al. (2009), who have not found any prognostic role of ER protein expression in 447 resected primary lung adenocarcinoma, we have surprisingly found significant results obtained by using the RNA extraction and target gene determination approach described below.
Markers predicting tumor response can function as sensitive short-term surrogates of long term outcome. Response to primary chemotherapy is an excellent experimental model to study the efficacy of anticancer therapy in a relatively short period of time. Moreover, the molecular analysis of pre- and post-chemotherapy tumor specimen enables the identification of chemotherapy resistant tumor cell subpopulation and thereby leads to adapted treatment options. However the identification of relevant resistance mechanisms in such settings and development of tests that could be used to detect these underlying resistance mechanisms for patient selection before therapy in clinical routine tissue have not succeeded so far. The use of such markers can make therapeutic strategies more effective for the individual patient and will allow changing regimen early in the case of non-responding tumors. Moreover, the identification of such markers has the potential to identify new drug targets and develop new and more effective treatments.
Lung cancer is commonly treated by chemotherapy, radiotherapy, or surgery with adjuvant chemotherapy. While hormonal therapies are commonly used in the treatment of endocrine organ-associated malignancies such as breast and prostate cancer, at present they are not indicated for lung cancer cases.
Ovarian cancer is the most lethal gynecologic cancer with 20,000 new cases per year and 15,000 deaths per year in the US (5 year overall survival: Stage I 80%, Stage IV 20%) in part due to the fact that most cases are detected in the late stages III and IV). Chemotherapy is standard of care for early and advanced ovarian cancer, while endocrine therapy is given only after failure of chemotherapy regimens. Response to chemotherapy is comparatively low with about 10%-30% of patients having benefit from treatment, while having serious side effects and being costly for the national health systems. Despite prominent responses towards chemotherapy, the survival of particularly ovarian cancer patients is still very poor. To date there are no reliable response markers to predict response to chemotherapy or endocrine therapy in ovarian cancer based on immunohistochemistry, FISH or expression profiling analysis. However, there are only few data addressing the molecular prediction of response to therapy in ovarian cancer.
Prostate cancer is the most frequent male cancer with approximately 190,000 new cases per year in the United States. However, in contrast to the situation in lung and ovarian cancer, most tumors are identified in an early and yet good prognostic stage. Compared to the high incidence rate the annual death rate is therefore comparably low with approximately 30,000 deaths. For most prostate cancer patients “watchful waiting”, i.e., sparing patients surgery, radiation and systemic treatment would be the most appropriate way to treat prostate cancer patients, as the individual risk of distant metastasis and death is very low (=“progression risk”). This is of particular importance given the higher age and comorbidities of prostate cancer patients. Moreover, therapeutic approaches to treat prostate cancer all bear a high risk of developing significant and persistent side effects, such as incontinence and impotence in about 80% of the cases. However, there are no reliable markers that might be useful to reliably identify patients of low progression risk and be useful for tailored treatment approaches. A particular problem is the high heterogeneity and dispersed growth of prostate cancer. Biopsying and subsequent tissue analysis is therefore only of limited efficacy and prognostic value.
Despite state of the art chemo- and endocrine therapy, more than 15% of all breast cancer patients metastasize early and die within the first three to five years after initial surgery. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. However, 30% of breast cancer patients suffer from recurring disease even after harsh chemotherapeutic and endocrine treatment and 15% of the patients die within four years after primary surgery.
In general, all patients of a given cohort do receive the same treatment, even though many will fail in treatment success. Markers predicting tumor response can function as sensitive short-term surrogates of long-term outcome. The use of such markers can make chemotherapy more effective for the individual patient and will allow changing regimen early in the case of non-responding tumors.
Although much effort has been devoted in developing an optimal clinical treatment course for individual patients with cancer, very little progress has been made in predicting the individual's response to a certain treatment. Currently, the probability of response of patients to a certain cancer treatment is usually determined by measuring the status of a marker on protein-level by immunohistochemistry (IHC). Assays based on protein-level measurements exhibit only limited quantitative performance and comparatively high inter- and intra-assay variabilities. Especially immunohistochemistry often yields different results in different laboratories. IHC assays have the added drawback that they often need to be evaluated by trained pathologists or other personnel, thus adding a subjective component to the determination of assay results.
Other approaches, as FISH (Fluorescence In Situ Hybridization) or expression profiling analysis, suffer of drawbacks as low sensitivity, restriction of sample preparation and restricted multiplexing capabilities.
Chemotherapy is standard of care for early and advanced lung cancer, while endocrine therapies have not been tested in this cancer indication. To date there are no reliable response markers to predict response to chemotherapy or endocrine therapy in lung cancer based on immunohistochem-istry, FISH or expression profiling analysis. So, it is yet difficult to determine those patients suffering of lung cancer who will respond to a certain therapy.
Similarly, in ovarian cancer endocrine therapies have not been tested in early treatment stages. Lack of reliable response markers and failure of immunohistochemical methods to determine the prognostic value of hormone receptors has corrupted these developments. In contrast in breast and prostate cancer the endocrine treatment options are standard of care as being one of the most effective treatment options. Here, the reasons for failure of endocrine treatment, is still not well understood.
The present invention surprisingly opens a new approach to diagnostic assessment of cancer and also suggests the possibility of endocrine therapy for cancer patients. Moreover it enables a new kind of cancer tumor classification into the principle underlying biological activities and therefore a general risk categorization resembling to some extent the current situation in breast cancer.